title: Expression of the endothelin axis in noninvasive and superficially invasive bladder cancer: relation to clinicopathologic and molecular prognostic parameters.
abstract: BACKGROUND
  The endothelin (ET) axis plays a role in cancer biology and plays a potential role as a target for molecular therapy in urogenital tumours. Alterations of several proteins of the ET axis were detected in invasive bladder cancer.
  
  
  OBJECTIVE
  To examine the potential role of the expression of ET axis proteins compared to other prognostic parameters (kinase inhibitor 67 [Ki-67], tumour protein 53 [TP53], and fibroblast growth factor receptor 3 gene [FGFR3] mutations) in noninvasive and invasive bladder cancer.
  
  
  METHODS
  Tissue microarrays from 154 consecutive patients with pTa-pT2 urothelial bladder cancer were immunohistochemically stained for endothelin 1 (ET-1), endothelin A and B receptors (ET(A)R, ET(B)R), TP53, and Ki-67. FGFR3 mutations were detected by SNaPshot analysis.
  
  
  METHODS
  The results were correlated with clinicopathologic parameters and disease-specific survival, overall survival, and recurrence-free survival.
  
  
  CONCLUSIONS
  Proteins of the ET axis were frequently expressed in bladder cancer (ET-1 in 62% of tumours, ET(A)R in 93% of tumours, and ET(B)R in 84% of tumours). ET-1 expression was strongly correlated with tumour stage (p=0.015), histologic grade (p=0.008), and low proliferation status (p=0.003). ET(A)R immunostaining was only associated with low proliferation status (p=0.015). Kaplan-Meier survival analysis showed a significantly longer overall survival for patients with ET-1-expressing tumours (p=0.007). A significantly longer disease-free survival was found in patients with ET(A)R-expressing tumours (p=0.040), whereas ET(B)R expression was significantly correlated to a longer disease-free survival only in subgroups of patients with multifocal tumours (p=0.031), low proliferation index (Ki-67 ≤10; p=0.050), low TP53 expression (≤10; p=0.018), and tumours with an FGFR3 mutation (p=0.026). In the global model for recurrence-free survival, only high-grade (p=0.048) and negative ET(A)R immunoreactivity (p=0.048) were correlated with poor prognosis.
  
  
  CONCLUSIONS
  In addition to other factors, particularly age at diagnosis and growth pattern, lack of ET-1 expression may be an independent negative prognostic factor for the overall-survival probability of bladder cancer patients. Lack of ET(A)R expression may be an independent negative marker for recurrence-free survival.
authors.affiliation: Institute of Pathology, University of Muenster, Muenster, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Eltze
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
authors.forename: Christian
authors.initials: C
authors.lastname: Wülfing
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Zwarthoff
authors.forename: Maximilian
authors.initials: M
authors.lastname: Burger
authors.forename: Robert
authors.initials: R
authors.lastname: Stoehr
authors.forename: Eberhard
authors.initials: E
authors.lastname: Korsching
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D002277:Carcinoma / Q000737:chemistry* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D016009:Chi-Square Distribution; D018572:Disease-Free Survival; D019332:Endothelin-1 / Q000032:analysis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D009154:Mutation; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D044022:Receptor, Endothelin A / Q000032:analysis*; D044023:Receptor, Endothelin B / Q000032:analysis; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D001749:Urinary Bladder Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D019459:Urothelium / Q000737:chemistry / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D019332:Endothelin-1; D019394:Ki-67 Antigen; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3